Method of handling sterile liquids



' Feb. 15, 1949. N. M. NESSET Y v k I I \n Feb. 15, 1949. M. E-r 2,461,837

METHOD OF HANDLING STERILE LIQUIDS Filed Sept. 22, 1945 2 Sheets-Sheet 2 Patented Feb. 15, 1949 METHOD OF HANDLING STERILE LIQUIDS Naurice M. Nesset, Glenview, Ill., assignor to Baxter Laboratories, Inc., Glenview, 111., a corporation of Delaware Application September 22, 1943, Serial No. 503,405

This invention relates to a method of handling sterile liquids, and more particularly to the handling and treating of liquids and maintaining the liquids in sterile condition in the course of handling and treatment.

An object of the invention is to provide methods for the reception, storage and dispensing of sterile liquids. Another object is to provide methods for introducing sterile liquids into containers, maintaining the liquids within the containers in sterile condition, and dispensing the sterile liquids from the containers. A further object is to provide a method for receiving blood, storing the same in-sterile condition, and thereafer dispensing the blood. Yet another object is to provide for the handling of parenteral solutions and for the storage and dispensing of such solutions.

Another object of the invention is to provide a method for the drying and storing of products, such as biologics, and the re-forming of such products as solutions, and the dispensing of the solutions. Yet another object is to provide in such a method for the maintaining of the solutions under sterile conditions. Still a further object is to provide a method for introducing solid materials into solutions which have been maintained in sterile condition prior to the dispensingof the solutions.

Another object of the invention is to provide a method for the handling and treatment of sterile liquids in which the material being treated is maintained in sterile condition throughout a series of operations and in which the liquid is introduced into a container through a closure having a self-sealing diaphragm and is withdrawn from the container through a passage in the closure which is opened by removing a removable plug from the passage.

Other features and advantages will appear from the following specification and drawings, in-

which- Fig. 1 is a plan view of the closure in position on a container; Fig. 2 is a vertical sectional view taken along the line 2-2 of Fig. 1; Fig 3 is a vertical-sectional view taken through another portion of the closure and along the line 3-3 of Fig. 4; Fig. 4 is a plan view of the closure alone; Fig. 5 is a vertical sectional view of the closure in position on a container and showing a needle extending therethrough for the introduction of liquids into the container; Fig. 6 is a vertical sectional view of a container having the closure therein and arranged for the dispensing of blood from the container; Fig. 7 is a transverse sectional view taken along the line 1-1 of Fig. 6;

5 Claims. (Cl. 128-272) and Fig. 8 is a vertical sectional view of a modified form of closure.

In the embodiment of the invention shown in- Figs. 1 to 7, A designates a container; B, a resilient closure for the neck of the container; and C, a removable sealing means.

The container'A may be of any suitable type.

As illustrated, the container is of glass and is of the general type shown in Baxter Patent No. 2,004,027, the bottom of the container being adapted to receive and support a bail member (not shown) by which the container can be supported in inverted position for the withdrawal of liquids.

. The container neck A may be provided with beads or threads for the purpose of confining a cap thereon. In the specific illustration given,

the container neck is provided with threads I0 and a bead.

The closure B may be of any suitable construc- I tion and resilient material. I prefer to employ a resilient rubber material which is quite elastic and which forms a good seal with the neck of th container A. The plug B is provided on its upper side with an integral flange l I which rests upon the top of the container neck. An interrupted or short passage I4 extends partially through the blood and is closed by a thick integral diaphragm 13 which extends across the upper portion of the plug and across the top of the passage l4? The corresponding aligned portion of the plug immediately over the passage l4 may be marked at l2 with an X or some other indicating means to enable the operator to locate the passage M from above and pass a needle through the plug into the passage [4. e v

The thick integral diaphragm l3 which extends across the portion of the plug B above the passage l4 should be self-sealing after being punctured with a hypodermic needle. Thus, when the integral diaphragm I3 is punctured with an 18 gauge steel needle and the needle is withdrawn therefrom, the diaphragm l3 effectively closes the opening which was formd by the needle and means of the clamp member IB which may be formed from aluminum or other metal and which is spun into the position shown. It will be observed that the clamp member on its lower side engages the lower bead whereby it is firmly locked in position. If desired, the threads Ill may be omitted and beads employed only near the lower portion of the bottle neck. With this construction, the inner seal I5 can be removed by tearing and, if desired, a portion of clamp It may be cut away along its upper flange to facilitate the grasping of the seal I5 to aid in its removal. If desired, the inner clamp I5 may also be provided with a tear flap to enable it to beseparated from the container neck.

Above the clamp 16, I provide another resilient seal I8, which is identical to seal I5 and which provides an uncontaminated and sterile surface on the seal so that the sterile hollow needle may be passed through plug B and seal I5 without becoming contaminated and thus obviating the danger of contaminating the interior of the container. Above the seal I8 is a metaldisk I9, and above the disk I9" is an outer cap 20. Cap is provided with a tear tab 2| and it has its lower portion spun about the lowerbcad of the threads Ill so as to confine it in position.

In addition to the passages described, the container B is provided with a cone-shaped seat 22 adapted to receive a correspondingly shaped cone valve 23. Below the seat 22, a passage 24 establishes communication with the interior of the container. It will be noted that the valve body 23 fits loosely within the seat 22 and may be lifted slightly under vacuum to permit the escape of vapors, etc. On the other hand, it has a smooth junction with the seat 22 so as to form an airtight seal therewith when pressure is exerted upon member 23.

Liquid may be introduced into the container by passing a hollow needle 24 through the selfsealing diaphragm I3 above the passage I4. For this operation, the cap 20 and metal disk I9 are removed from the closure. As seen in Fig. 5, the needle may be mounted on a valve 25 or any suitable or conventional construction for controlling the flow of blood through the needle and into the container A.

In the dispensing of liquids from the container A, as seen particularly in- Figs. 6 and 7, the clamp It, the cap 243, the metal disk I9, and the resilient seals I8 and I5 may be removed from the plug B. The valve plug 23 may also be removed from the plug B. A needle 26 may be passed through the selfsealing diaphragm I3 above the passage I4 so that the needle extends into the passage and into the container.

A dispensing adapter or fitting 21 may be provided adjacent its end with a pair of spaced enlargements 28 and 29 and at its end with a filter to of suitable construction. As illustrated, the filter 39 may be in the form of a stainless mesh filter, cylindrical in shape and having one end of the cylindrical portion thereof closed by the mesh as at 3!. The filter may be equipped with a bead at the open end thereof which is adapted to be received in relasable locking engagement With the end or the adapter Zl. As illustrated in Fig. 7, the end 32 of the adapter 21 may be provided with a pair of opposed flanges 33 and 34 which may be engaged by the bead on the filter 38. To the adapter 21 may be attached rubber tubing 35 or other suitable means for conducting the liquid from the adapter.

In the construction and arrangement illustrated in Fig. 6, the needle 26 serves to introduce air into the container while the blood is withdrawn through the filter 30 and adapter 21 to the rubber tubing 35.

In the modified form of the invention shown in Fig. 8, the closure plug B is equipped with a passage 36 therein and a thin integral diaphragm 3'! extending? across the upper portion of the passage. Preferably, as illustrated, the thin integral diaphragm 31 is spaced very slightly below the upper surface of the plug. The walls of the passage 36 may be constricted as at 38 below the diaphragm 31 so as to provide a shoulder 39 therebelow. In this construction, the plu may be provided with a passage M and a thick integral diaphragm I 3 thereover corresponding exactly to the passage and self-sealing diaphragms shown in Figs. 1 to 7. This plug may also be provided with a passage and a removable valve plug corresponding exactly to the passage 24 and Valve plug 23 shown in the embodiment of Figs. 1 to 7. Thus, the closure plug B, shown in Fig. 8, may be of exactly the same construction as the plug shown in Figs. 1 to 7 except for the provision of the additional passage 36 therein.

The method of receiving, storing, and dispensing sterile liquids in accordance with the present invention may utilize the apparatus described herein. To illustrate the method of the invention, the handling of blood will be described as a specific example. In the handling of blood, the container is sealed under vacuum with a conventional anti-coagulant solution therein. The closure is in position on the container, as shown in Figs. 1 and 2. If desired, the vacuum may be created in the container by heating the anti-coagulant solution therein while the valve plug 23 is looselyseated on the seat provided by the plug B. Air and moisture vapor may escape about the removable plug 23. When the heating is stopped, the plu 23 will be seated and, as the moisture vapor within the container condenses, a vacuum will be formed therein. The plug .23 will effectively seal the container to maintain this vacuum. The remaining'closure equipmentmay then be applied.

When the blood is tobe introduced into the container, the cap 20 and metal disk I9 are removed and, as seen in Fig. 5, a needle is passed through the self-sealing. diaphragm I3. into the passage I4 and the container A. Blood from a donor or other source may then flow through the valve 25 and needle 24 into the container A, the vacuum within the container being used to draw the blood thereinto.

After the blood has been drawn into the container, the valve 24 is removed from the plug B and the self-sealing diaphragm I3 closes the opening so as to effectively seal the container. The blood is then maintained under sterile conditions and the container remains sealed under the residual vacuum which remains after drawing the blood into the container.

When the blood is to be withdrawn from the container, the apparatus shown in Fig. 6 may be used. The cap 20, metal disk I9, the rubber seals I8 and I5, and clamping members I6 may all be removed from the plug B. A needle 26 may then be passed through the self-sealing insert I3. The removable valve plug 23 is removed from the plug B and the adapter 2'! is introduced into the passage 24 in the plug B. The spaced enlargements 28 and 29 engage the portions of the plug" B at the base of the seat for the valve '23 which has been removed. The filter on the end of the With this equipment, the blood may be han dled under completely sterile conditions. It may beintroduced into the container, maintained in sterile condition during storage, and withdrawn also under sterile conditions. a

The method may be applied in a similar manner for the dispensing of parenteral solutions. The parenteral solution maybe placed in the container and sterilized therein. The heating of the solution within the container to sterilizeit permits the creation ofv a vacuum within the container by reason of the flowof air and moisture vapor past the removable valve plug 23. When the container and solution are cooled, a vacuum is formed therein.

When the solution is to be dispensed, a fitting or adapter, such as the adapter 21, may be placed in the passage 24 from which the plug 23 is removed. In the case of parenteral solutions, the filter 30 on the end of the adapter may be omitted. The needle 26 may be passed through the self-sealin diaphragm 23 to introduce air into the container.

' A similar method may be utilized in connection with the modified form of plug B, shown in Fig. 8, which may be used for the handling of parenteral solutions, and if the plug is not to be reused the passage 36 may be used for the introduction of air into the container, In this case, the thin diaphragm 3'! will be ruptured by an air tube of suitable or conventional construction which may be placed therein. If desired, an air tube may be placed within the container itself and may extend intothe passage 36 and against the shoulder 39. In this case, the diaphragm 31 is ruptured, and air flows inwardly through the opening formed thereby.

Another application of the invention lies in the drying of biologics or other material. When it is desired to dry biologics, the closure cap and upper rubber seal [8 are removed. The liquid biologic is then drawn into the container through a hollow needle which is passed through the sealing member I 5, the plug B, and into an opening into passage M in the plug. Since a vacuum is furnished within the container, the liquid can be readily drawn at a controlled rate through a tube connected with the hollow needle until a desired amount is obtained within the container. When it is desired to dry the material now within the container, the remaining rubber seal I is removed and the top surface of the rubber plug and the cone valve 23 is sterilized with a suitable antiseptic, such as iodine, alcohol, and the like. The filled unit is then placed in the evacuated chamber, which is subsequently subjected to a high vacuum, the differential in pressures on the inside of the container and of the evacuated chamber being automatically adjusted by the same mechanism that obtained in the creation of a partial pressure in the first assembling of the container. Heat is applied and under the influence of temperature and the reduced pressure, the liquid portion of the contents is removed, leavingthe solid material within the container. The vapors from the liquid during this operation escape through the vertical passage around the cone valve 23 in exactly the same manner-as heretofore described for the removalof-air; Upon sudden release of the high vacuum in the evacuated chamber, the rubber cone seal is again firmly seated, hermetically sealing the container. The unit is then'removed from the chamber, the top surface being sterilized and a new sterile rubber seal I5 placed upon the top of the closure plug, followed with a metal disk, and the metal band spun into position, thus re-sealing the package for storage and transportation.

All of the above steps are accomplished in a desirable aseptic manner, permitting ease in han- When the dried material within the containeris to. be used, the outercover may be removed alongwith the metal and rubber disks. Using again'the hollow needle connected to a hollow tube, the desired fluid for causing a re-solution of the dried material is drawn into the container, utilizing the partial vacuum which was left in the container at the conclusion of the drying step. Inasmuch as all of the vacuum which was in the container is not utilized for drawing in the solvent, the residual partial pressure provides suflioient means for holding the cone sealin a sealing position so that when the tube and needle are removed after drawing in the solvent, there is still a hermetically sealed package which preserves the inherent asepsis and permits subsequent storage and transportation or the regenerated biologic.

For the dispensing of the regenerated material, the rubber cone seal 23 is readily removed, exposing a free hole into which is insertedthe prop-. er connection for withdrawal, and the container is inverted to permit the liquid to be dispensed. A proper air inlet into the unit for dispensation is created by puncturing the thin rubber stopper [3 in passage l2.

The above steps are illustrative of steps which may beyemployed with the new type of closure wherein the valve permits the withdrawal of air, moisture, vapors, etc., while at the same time by reason of its smooth connection with the cone seat, permits a quick re-sealing and the maintenance of vacuum within the container. It will be understood, however, that the closure has a great number of other uses which can be here enumerated. For example, the wide opening permits the introduction of certain solid materials into a container holding parenteral fluids for. solution immediately prior to dispensation. Due to the fact that certain solid drugs are unstable when in solution, precluding the possibility of making up such materials well in advance of requirement, the present closure offers a simple method for introducing such drugs into the container just before dispensation. Similarly, certain drugs do not withstand heat sterilization. With the present closure, the diluent may be sterilized first and 1 then such drugs may be aseptically introduced through the opening controlled by valve 23 into the container. It will further be noted that the men-sea ,7 asillustrative oi the uses to which the. structure may be put, it will be understood that such details of structure and such method stepsmay be widely varied without departing from the spirit of my invention.

I claim:

' 1. A method of handling blood, comprising heating a water solution of arr-anticoagulant within a container having an opening to sterilize the solution and cause water vapor to be withdrawn through the opening, sealing said opening, evacuating said container, and introducing blood into the evacuated container while the same is sealed against the ingress of air.

' 2. Ina method of, drying biologics and the like, the steps of drawing the liquid materialto be dried-into an evacuated container provided with an opening, sealing said opening against-the ingress of air while permitting the escape of vapors, heating and further evacuating the container to dry the material therein and to. cause. the vapors to escape through said. opening, and subjecting the exterior'of said container to atmospheric pressure to maintain said opening sealed against the ingress of air.

3. In a method oi drying biologics and the like, the steps of drawing the liquid material to be dried into an evacuated container having an opening, sealing said opening against the ingress of air while permitting the escape ofvapors, subjecting the exterior of the container to vacuum and. heat to cause they vapors of thematerial therein to be withdrawn through said openingand then subjecting theexterior of the container to atmospheric pressure to seal said opening against the ingress of air.

4, In a method of drying biologics and the like, the steps of drawing the liquid material to. be dried into an evacuated container provided with anopening, heating the container to cause vapors therein to pass through said opening, subjecting the exterior of said container to vacuum, then after the drying operation sealing said opening, and thereafter introducing liquid under the influence oithe vacuum within thecontainer into the vacuumto regeneratethe driedmaterial while maintaining the container in sealed condition.

5- In a method of drying biologics and the like, the steps of drawing the liquid material to be dried into an evacuated container provided with REFERENCES CITED The following references are of record in the file of this patent:

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